Obesity is a global health problem whose prevalence is increasing substantially due to lifestyle changes. This complex medical condition is frequently linked to serious metabolic complications and deregulation of hormonal axes, which lead to perturbed homeostasis in conditions of overweight. Different studies have suggested that obesity is often associated to hypogonadism, a reproductive disorder that might also promote metabolic alterations, thus setting a vicious circle in the generation/perpetuation of obesity co-morbidities. While the targets and molecular mechanisms underlying this phenomenon are still unknown, emerging evidence from experimental models of metabolic stress linked to hypogonadism strongly suggests the potential role of perturbations of hypothalamic Kiss1/NKB neurons. Likewise, the recently identified involvement of epigenetics in the control of Kiss1 expression at puberty, a crucial stage in sexual development that is metabolically gated, suggests also the contribution of these regulatory mechanisms to this phenomenon. In this context, this project aims to elucidate the pathophysiological relevance of epigenetic regulatory mechanisms in obesity-induced hypogonadism and their influence in the generation/ maintenance of the metabolic complications of overweight. To this end, we will characterize the time-course of alterations of key hormonal and epigenetic factors in preclinical models of obesity and will evaluate the contribution of epigenetic modifications in deregulation of hypothalamic Kiss1/NKB neurons in conditions of overweight. In addition, we will analyse the potential role of gonadal steroids in this phenomenon. This project will help to identify the molecular targets and epigenetic mechanisms responsible for the metabolic perturbations linked to obesity-induced hypogonadism, and will aid to define better tools for the treatment of these complications.
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